Tschan-Plessl Astrid, Stern Martin, Schmied Laurent, Retière Christelle, Hirsch Hans H, Garzoni Christian, van Delden Christian, Boggian Katia, Mueller Nicolas J, Berger Christoph, Villard Jean, Manuel Oriol, Meylan Pascal, Terszowski Grzegorz
Department of Hematology, University Hospital Basel, Switzerland.; Department of Biomedicine, University Hospital Basel, Switzerland.
Department of Biomedicine, University Hospital Basel, Switzerland.
Transplant Direct. 2016 Jun 17;2(7):e89. doi: 10.1097/TXD.0000000000000605. eCollection 2016 Jul.
Occurring frequently after solid organ and hematopoietic stem cell transplantation, cytomegalovirus (CMV) replication remains a relevant cause of mortality and morbidity in affected patients. Despite these adverse effects, an increased alloreactivity of natural killer (NK) cells after CMV infection has been assumed, but the underlying physiopathological mechanisms have remained elusive.
We used serial analyses of NK cells before and after CMV infection in kidney transplant recipients as an in vivo model for CMV primary infection to explore the imprint of CMV infection using every patient as their own control: We analyzed NK cell phenotype and function in 47 CMV seronegative recipients of CMV seropositive kidney grafts, who developed CMV primary infection posttransplant. Seronegative recipients of seronegative kidney grafts served as controls.
We observed a significant increase of NKG2C expressing NK cells after CMV infection (mean increase, 17.5%; 95% confidence interval [95% CI], 10.2-24.9, < 0.001), whereas cluster of differentiation (CD)57 expressing cells decreased (mean decrease, 14.1%; 95% CI, 8.0-20.2; < 0.001). Analysis of killer immunoglobulin-like receptor (KIR) expression showed an increase of cells expressing KIR2DL1 as their only inhibitory KIR in patients carrying the cognate ligand HLA-C2 (mean increase, 10.0%; 95% CI, 1.7-18.3; = 0.018). In C2-negative individuals, KIR2DL1 expression decreased (mean decrease, 3.9%; 95% CI, 1.6-6.2; = 0.001). As for activating KIR, there was no conclusive change pattern. Most importantly, we observed a significantly higher NK cell degranulation and IFNγ production in response to different target cells (target K562, CD107a: mean increase, 9.9%; 95% CI, 4.8-15.0; < 0.001; IFNγ: mean increase, 6.6%; 95% CI, 1.6-11.1; < 0.001; target MRC-5, CD107a: mean increase, 6.9%; 95% CI, 0.7-13.1; = 0.03; IFNγ: mean increase, 4.8%; 95% CI, 1.7-7.8; = 0.002).
We report evidence for an increased function of NK cells induced by CMV infection. This increased in vitro functionality was seen in NKG2C-positive and NKG2C-negative subsets, arguing for an NKG2C independent mechanism of action.
巨细胞病毒（CMV）复制在实体器官和造血干细胞移植后频繁发生，仍是受影响患者死亡和发病的一个相关原因。尽管有这些不良影响，但人们认为CMV感染后自然杀伤（NK）细胞的同种异体反应性会增加，但其潜在的生理病理机制仍不清楚。
我们将肾移植受者CMV感染前后的NK细胞进行系列分析，作为CMV原发感染的体内模型，以每个患者自身作为对照来探索CMV感染的印记：我们分析了47例接受CMV血清阳性肾移植的CMV血清阴性受者的NK细胞表型和功能，这些受者在移植后发生了CMV原发感染。接受CMV血清阴性肾移植的血清阴性受者作为对照。
我们观察到CMV感染后表达NKG2C的NK细胞显著增加（平均增加17.5%；95%置信区间[95%CI]，10.2 - 24.9，P < 0.001），而表达分化簇（CD）57的细胞减少（平均减少14.1%；95%CI，8.0 - 20.2；P < 0.001）。杀伤细胞免疫球蛋白样受体（KIR）表达分析显示，在携带同源配体HLA - C2的患者中，仅表达KIR2DL1作为其唯一抑制性KIR的细胞增加（平均增加10.0%；95%CI，1.7 - 18.3；P = 0.018）。在C2阴性个体中，KIR2DL1表达减少（平均减少3.9%；95%CI，1.6 - 6.2；P = 0.001）。至于激活型KIR，没有明确的变化模式。最重要的是，我们观察到针对不同靶细胞（靶细胞K562，CD107a：平均增加9.9%；95%CI，4.8 - 15.0；P < 0.001；IFNγ：平均增加6.6%；95%CI，1.6 - 11.1；P < 0.001；靶细胞MRC - 5，CD107a：平均增加6.9%；95%CI，0.7 - 13.1；P = 0.03；IFNγ：平均增加4.8%；95%CI，1.7 - 7.8；P = 0.002）时，NK细胞脱颗粒和IFNγ产生显著更高。
我们报告了CMV感染诱导NK细胞功能增强的证据。这种体外功能增强在NKG2C阳性和NKG2C阴性亚群中均可见，表明存在一种不依赖NKG2C的作用机制。
